Impaired central tolerance induces changes in the gut microbiota that exacerbate autoimmune hepatitis.
Impaired central tolerance induces changes in the gut microbiota that exacerbate autoimmune hepatitis.
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DOI：
10.1016/j.jaut.2022.102808
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发表时间：
2022-04
影响因子：
12.8
通讯作者：
Alexandropoulos K
中科院分区：
文献类型：
--
作者：
Centa M;Weinstein EG;Clemente JC;Faith JJ;Fiel MI;Lyallpuri R;Herbin O;Alexandropoulos K
髓样胸腺上皮细胞（mTECs）通过消除自身反应性胸腺细胞诱导胸腺T细胞耐受。共生菌对于形成肠道和远端器官的T细胞反应也至关重要。我们之前的研究表明，mTECs （Traf6ΔTEC）缺失的小鼠产生自身反应性T细胞并发展为自身免疫性肝炎（AIH）。在本报告中，我们发现toll样受体（TLR）介导的对肝脏造血细胞和肠道微生物群的微生物感知有助于Traf6ΔTEC小鼠AIH的发展。虽然在免疫缺陷小鼠中过继转移胸腺Traf6ΔTEC T细胞足以导致AIH的发展，但用Traf6ΔTEC微生物群定殖无菌小鼠未能诱导AIH，这表明肠道微生物群有助于AIH的发展，但不是AIH发展的充分条件。微生物介导的AIH恶化与肝脏Foxp3+ T细胞数量增加有关，其增加与炎症程度成正比。肠道微生物群对AIH发展的贡献与微生物特征的改变有关，其组成受到胸腺T细胞区室的定性性质的影响。这些结果表明，胸腺中T细胞的异常选择可以诱导肠道微生物群的变化，从而导致器官特异性自身免疫和AIH的恶化。我们的研究结果增加了我们对AIH发展机制的理解，并为开发治疗这种疾病的新治疗方法创造了一个平台。
Medullary thymic epithelial cells (mTECs) induce T cell tolerance in the thymus through the elimination of self-reactive thymocytes. Commensal bacteria are also critical for shaping T cell responses in the gut and distal organs. We previously showed that mice depleted of mTECs (Traf6ΔTEC) generated autoreactive T cells and developed autoimmune hepatitis (AIH). In this report, we found that Toll-like receptor (TLR)-mediated microbial sensing on liver hematopoietic cells and the gut microbiota contributed to AIH development in Traf6ΔTEC mice. While adoptive transfer of thymic Traf6ΔTEC T cells in immune-deficient mice was sufficient for AIH development, colonization of germ-free mice with Traf6ΔTEC microbiota failed to induce AIH, suggesting that the gut microbiota contributes to but is not sufficient for AIH development. Microbiota-mediated exacerbation of AIH associated with increased numbers of hepatic Foxp3+ T cells and their increase was proportional to the degree of inflammation. The contribution of the gut microbiota to AIH development associated with an altered microbial signature whose composition was influenced by the qualitative nature of the thymic T cell compartment. These results suggest that aberrant selection of T cells in the thymus can induce changes in the gut microbiota that lead to exacerbation of organ-specific autoimmunity and AIH. Our results add to our understanding of the mechanisms of AIH development and create a platform towards developing novel therapeutic approaches for treating this disease.
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影响因子：
17.1
作者：
Faith JJ;Ahern PP;Ridaura VK;Cheng J;Gordon JI
通讯作者：
Gordon JI
DOI：
10.1126/science.1198469
发表时间：
2011-01-21
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Atarashi K;Tanoue T;Shima T;Imaoka A;Kuwahara T;Momose Y;Cheng G;Yamasaki S;Saito T;Ohba Y;Taniguchi T;Takeda K;Hori S;Ivanov II;Umesaki Y;Itoh K;Honda K
通讯作者：
Honda K
影响因子：
4.4
作者：
Haribhai, Dipica;Lin, Wen;Chatila, Talal A.
通讯作者：
Chatila, Talal A.
影响因子：
24.5
作者：
Donaldson, PT
通讯作者：
Donaldson, PT
影响因子：
--
作者：
Gordon J;Xiao S;Hughes B 3rd;Su DM;Navarre SP;Condie BG;Manley NR
通讯作者：
Manley NR